This phase II trial tests adding VSV-IFNβ-NIS to standard of care ipilimumab and nivolumab for the treatment of clear cell renal cell carcinoma that may have spread from where it first started to nearby tissue, lymph nodes, or distant parts of the body (advanced) or that has spread from where it first started (primary site) to other places in the body (metastatic). A virus modified in the laboratory, such as VSV-IFNβ-NIS, may be able to kill tumor cells without damaging normal cells. Immunotherapy with monoclonal antibodies, such as ipilimumab and nivolumab, may help the body's immune system attack the cancer, and may interfere with the ability of tumor cells to grow and spread. Giving VSV-IFNβ-NIS with ipilimumab and nivolumab may be effective for the treatment of advanced or metastatic clear cell renal cell carcinoma.

Inclusion Criteria:

• Age ≥ 18 years

• Disease Characteristics:

  • Histological confirmation of advanced (not amenable to curative surgery or radiation therapy) or metastatic [American Joint Committee on Cancer (AJCC) version 8 Stage IV] renal cell carcinoma (RCC) with a clear cell component, including all International Metastatic RCC Database Consortium (IMDC) risk categories (favorable, intermediate, and poor risk) allowed

• Measurable disease as defined by Response Evaluation Criteria in Solid Tumors (RECIST) 1.1.

  • NOTE: Liver lesions that have been previously embolized (bland embolization, chemo- or radio-embolization) or have undergone percutaneous thermoablation are not eligible as target lesions. Tumor lesions in a previously irradiated area are not considered measurable disease; disease that is measurable by physical examination only is not eligible

• Eastern Cooperative Oncology Group (ECOG) performance status (PS) 0, 1 or 2

• Hemoglobin ≥ 9.0 g/dL (obtained ≤ 15 days prior to registration)

• Absolute neutrophil count (ANC) ≥ 1500/mm^3 (obtained ≤ 15 days prior to registration)

• Platelet count ≥ 100,000/mm^3 (obtained ≤ 15 days prior to registration)

• Total bilirubin ≤ 1.5 x upper limit of normal (ULN) (obtained ≤ 15 days prior to registration)

• Alanine aminotransferase (ALT) and aspartate transaminase (AST) ≤ 3 x ULN (≤ 5 x ULN for patients with liver involvement) (obtained ≤ 15 days prior to registration)

• Prothrombin time (PT)/international normalization ratio (INR)/activated partial thromboplastin time (aPTT) ≤ 1.5 x ULN OR if patient is receiving anticoagulant therapy and INR or aPTT is within target range of therapy (≤ 5 x ULN for patients with liver involvement) (obtained ≤ 15 days prior to registration)

• Serum creatinine ≤ 1.5 x upper limit of normal (ULN) OR creatinine clearance ≥ 50 ml/min using the chronic kidney disease epidemiology (CKD-EPI) creatinine equation (per National Kidney Foundation) (obtained ≤ 15 days prior to registration)

  • NOTE: See calculator at National Kidney Foundation website here: https://www.kidney.org/professionals/kdoqi/gfr\_calculator

• Negative pregnancy test done ≤ 8 days prior to registration, for persons of childbearing potential only

• Provide written informed consent

• Willingness to provide mandatory blood specimens for correlative research

• Willingness to provide mandatory tissue specimens for correlative research

• Willing to return to Mayo Clinic for follow-up (during the active monitoring phase of the study)

Exclusion Criteria:

• Any of the following because this study involves an investigational agent, the genotoxic, mutagenic and teratogenic effects of which on the developing fetus and newborn are unknown:

  • Pregnant persons
  • Nursing persons
  • Persons of childbearing potential and persons able to father a child who are unwilling to employ adequate contraception

• Prior treatment for advanced or metastatic RCC [American Joint Committee on Cancer (AJCC) Stage IV]

• History of portal vein thrombosis involving more than intrahepatic portal vein branches: thrombosis of the right or left portal vein branch or the bifurcation, partial or complete obstruction of the portal vein trunk

  • NOTE: Level 0 or 1 tumor thrombus remain eligible; Level 2, 3, of 4 tumor thrombus related to the primary kidney tumor are ineligible

• Has received a live vaccine ≤ 30 days prior to registration

  • NOTE: Seasonal influenza vaccines for injection are generally inactivated flu vaccines and are allowed; intranasal influenza vaccines (e.g., Flu-Mist®) are live attenuated vaccines and are NOT allowed

• Any of the following prior therapies:

  • Surgery ≤ 3 weeks prior to registration
  • Chemotherapy ≤ 2 weeks prior to registration
  • Radiation therapy ≤ 2 weeks prior to registration
  • Therapy in the first-line setting for advanced or metastatic RCC
  • Adjuvant immunotherapy during which or in the ≤ 6 months immediately following, relapse or disease progression has occurred

• New York Heart Association classification III or IV, known symptomatic coronary artery disease, or symptoms of coronary artery disease on systems review, or known cardiac arrhythmias [atrial fibrillation or supraventricular tachycardia (SVT)]

• Co-morbid systemic illnesses or other severe concurrent disease which, in the judgment of the investigator, would make the patient inappropriate for entry into this study or interfere significantly with the proper assessment of safety and toxicity of the prescribed regimens

• Uncontrolled intercurrent illness including, but not limited to:

  • ongoing or active infection
  • symptomatic congestive heart failure
  • unstable angina pectoris
  • cardiac arrhythmia
  • dyspnea at rest due to complications of advanced malignancy or other disease that requires continuous oxygen therapy
  • or psychiatric illness/social situations that would limit compliance with study requirements

• Current immunodeficiency or immunosuppression and receiving systemic corticosteroids at > 10mg/day prednisone or equivalent ≤ 1 week prior to registration.

  • NOTE: Inhaled steroids for pulmonary disease are permitted

• Known history of the following:

  • Suspected active organ-threatening autoimmune disease including, but not limited to, inflammatory bowel disease, autoimmune hepatitis, lupus, or pneumonitis which can flare while receiving immune checkpoint inhibitor (ICI) treatment.

    • NOTE: Patients with well-controlled or clinically inactive autoimmune diseases are eligible

  • Non-infectious pneumonitis that required steroids, current pneumonitis, carcinomatous meningitis, or interstitial lung disease that is symptomatic or may interfere with the detection or management of suspected drug-related pulmonary toxicity

• Known or ongoing illness or infection including:

  • Any active Grade 3 or higher [per the National Cancer Institute (NCI) Common Terminology Criteria for Adverse Events (CTCAE), version (v) 5.0] viral, bacterial, or fungal infection ≤ 2 weeks of registration.

  • Acute hepatitis B (HBV) or acute hepatitis C virus (HCV)

    • NOTE: Patients with chronic HBV or HCV with adequate liver function per inclusion criteria are still eligible

  • Patients known to be HIV positive and currently receiving antiretroviral therapy

  • Known history of active tuberculosis (TB) (bacillus tuberculosis)

  • Uncontrolled hypertension and/or diabetes

  • Clinically significant pulmonary disease (e.g., chronic obstructive pulmonary disease requiring hospitalization ≤ 3 months prior to treatment)

• Receiving concurrent anti-cancer therapy (chemotherapy, immunotherapy, radiotherapy, or any other investigational agent or therapy considered investigational (used for a non-Food and Drug Administration (FDA) approved indication and in the context of a research investigation)

• Known concurrent malignancy that is progressing or requires active treatment

  • EXCEPTIONS: basal cell carcinoma of the skin, squamous cell carcinoma of the skin, in-situ cervical cancer that has been treated with curative intent, prostate cancer confined to the prostate gland with Gleason score ≤ 6, as well as any cancer treated with curative intent or any prior cancer with a disease-free interval of ≥ 3 years

• History of myocardial infarction ≤ 6 months, or congestive heart failure requiring use of ongoing maintenance therapy for life-threatening ventricular arrhythmias